The present invention relates to novel antioxidative Vitamin B6 analogs and their use in the cosmetic, dermatological, pharmaceutical and/or nutritional fields.
Skin is subject to insults by many extrinsic and intrinsic factors. Extrinsic factors include ultraviolet radiation (e.g., from sun exposure), environmental pollution, wind, heat, low humidity, harsh surfactants, abrasives, and the like. Intrinsic factors include chronological aging and other biochemical changes from within the skin. Whether extrinsic or intrinsic, these factors result in visible signs of skin aging and environmental damage, such as wrinkling and other forms of roughness (including increased pore size, flaking and skin lines), and other histological changes associated with skin aging or damage.
In recent years, intrinsic factors contributing to the premature aging of skin have been investigated. Substances having anti-oxidizing activity, those having an activity of scavenging reactive oxygen species or radicals, or an activity of inhibiting the generation of reactive oxygen species in the presence of a metal ion (Fenton reaction) have attracted attention, because reactive oxygen species or radicals are responsible for a variety of diseases as well as the aging of skin such as hardening, development of wrinkles and pigmentation, and the generation of reactive oxygen species in the presence of metal ion causes the oxidative disorders in the body which are responsible for a variety of diseases and the aging of skin described above.
Additionally, free radicals also have been associated with the development of tumors. It is believed that free radicals damage DNA and change the normal cells into potential tumor cells.
One effort to reduce the signs of aging that has received attention in recent years is the use of alpha-hydroxy acids (AHAs). Products with AHAs are marketed for a variety of purposes: to smooth fine lines and surface wrinkles, to improve skin texture and tone, to unblock and cleanse pores, to improve oily skin or acne, and to improve skin condition in general. Cosmetics that contain AHAs have become widely used in recent years despite many unanswered questions about their safety. Recently, a study sponsored by the cosmetics industry indicates that these products may make users more sensitive to sunlight and especially to the ultraviolet (UV) radiation component of sunlight. UV exposure can damage the skin and at high doses, especially over a long period, can cause skin cancer. Thus, it would be advantageous, for example, for cosmetics containing alpha-hydroxy acids to contain a UV protectant.
Patient compliance refers to the extent to which actual behaviour of a patient coincides with medical advice. Approximately two-thirds of patients do not follow their doctor""s advice. Some of the reasons for not taking the medication as prescribed are complexity of drug regimen, embarrassment, e.g., children who need to take medications at school, and forgetfulness. Thus, an easy method of treatment of diseases would be desirable.
Thus, it would be desirable to have a compound that is easily applied or administered which would provide (1) benefit to the skin, (2) treatment of diseases, (3) an advantageous means of drug/vitamin delivery and/or (4) cosmotological enhancements.
The invention concerns new vitamin B6 analogs with antioxidative, radical-scavenging functions which counteract pathophysiological disorders especially connected with aging processes. The new agents counteract against oxidation- and age-mediated, acquired and inherited disease-related pathophysiological disorders. These functions render the new analogs useful for the treatment of these disorders which include but are not limited to multiple sclerosis, degenerative cell, tissue and organ processes, gerontological diseases such as Alzheimer""s disease, Diabetes Type I, allergies, neurological disorders, skin diseases such as psoriasis, bone and bone tissue disorders such as osteoporosis. The new analogs are also antidotes against organo-phosphorous compounds.
The new compounds are also suitable for the treatment of disorders associated with defects of the vitamin B6 metabolism and therefore act as vitamin B6 antagonists.
The analogs of this invention have important anti-infective potential, for example antiviral activity, antiparasitic activity, and antifungal activity. Especially useful are the analogs of the invention for the treatment of viral diseases caused by enveloped viruses such as hepatitis, herpes and retro viruses but are also useful for the treatment of other viral infections, such as infection from influenza or rhinovirus.
The new agents have cytoprotecting, immunomodulating, stimulating and inhibiting activity in vitro, suppress cell proliferation in cancer cells and cause cell death in these cells.
These functions enable the new compounds to be useful for cosmetic or cosmeceutical or nutritional applications, keratological or skin-caring applications such as skin protection and skin restoration, in improving health, fitness, hygiene of the human and animal body, skin, teeth, oral gums, nails, lips and hair. The new analogs are also useful agents for the treatment and prevention of sun or skin bums. In addition, the new analogs may be used as protecting dyes. The new analogs are also useful agents for the release of vitamins. They aid in the transport of pharmaceutical, cosmeceutical and cosmetic agents into cells, in particular specialized cells. As the new analogs are dephosphorylated by endogenous phosphorylases they will be transported into the cells where they are rephosphorylated and unable to pass out of the cell in phosphorylated form.
Toxic or cytopathic effects have not been observed with the analogs of this invention in a number of cell culture systems. It appears that the new analogs act as relatively untoxic polyspecific drugs with an amphoteric structure, as multiplex buffer molecules.
The new analogs have the general formula (Formula I) 
wherein
R1 is hydrogen, or acyl with 2-22 carbons (excluding retinoyl);
R2 is hydrogen, or aryl with 6-30 carbons; provided that at least one of R1 or R2 is not hydrogen;
X1, X2 and X3 are independently O, S, or NR3;
R3 is hydrogen, alkyl with 1-6 carbons, or acyl with 2-6 carbons;
Y is O, S, or NH;
Z is CH or N;
and include salts and common esters derived from unreacted remaining functional groups in Formula I. In a preferred embodiment X1 is O, X2 is NH, X3 is S, Z is CH and Y is S.
The salts and common esters selected do not in a substantial way adversely affect the therapeutic, cosmetic, hygiene, anti-aging, cosmeceutical and nutritional functions of the new analogs.
Analogs in which R1 is an xcex1-hydroxy acid such as glycolic or lactic or malic acid residue and their common salts and esters are preferred. Also preferred are analogs in which R1 is derived from an FDA approved or accepted agent such as carminic acid and their common salts and esters. Carninic acid is a coloring agent approved by the FDA in foods and drugs. Also preferred are analogs in which R1 is derived from an FDA approved or accepted agent, a vitamin such as pantothenic acid which analogs may function as Vitamin B3 or B5 delivering agents or ascorbic acid (Vitamin C) and their common salts and esters. Also preferred are analogs in which R1 is derived from glucuronic acid or a glucuronic acid derivative such as hyaluronic acid with a molecular weight of 5xc3x97104 to 8xc3x97106 and their common salts and esters.
More preferred is a subgroup of analogs in which R1 has the above meanings and R2 is hydrogen and their common salts and esters.
Most preferred in this subgroup are analogs in which Z is CH, X1 is oxygen, X2 is NH, X3 and Y are S, and their salts and common esters which do not in a substantial way adversely affect the therapeutic, cosmetic, hygiene, anti-aging, cosmeceutical and nutritional functions of the compounds in the subgroup.
Analogs in which R2 is derived from a phenolic hydroxy group containing derivative such as phenol are preferred and their common salts and esters. Also preferred are analogs in which R2 is derived from phenolic hydroxy group containing derivative such as xcex1-tocopherol and their common salts and esters. Also preferred are analogs in which R2 is derived from a coenzyme such as ubiquinone and their common salts and esters.
More preferred is a subgroup of analogs in which R2 has the above meanings and R1 is hydrogen and their common salts and esters. Most preferred in this subgroup are analogs in which Z is CH, X1 is oxygen, X2 is NH, X3 and Y are S and their salts and common esters which do not in a substantial way adversely affect the therapeutic, cosmetic, hygiene, anti-aging, cosmeceutical and nutritional functions of the compounds in the subgroup.
The analogs radical-scavenging function reduces the concentration of radicals nitrogen-containing radicals such as nitric oxide, their epigones (peroxinitrite S-nitrosothiols), the hydroxyl radical, the superoxide anion radical, singlett oxygen; they act as nitric oxide synthetase inhibitor and thus display general anticancer activity where the cancer is caused or believed to be caused by cancerogenic radicals. Therefore, the analogs of this invention act as antileukemic, anti-breast cancer, anti-skin cancer active compounds. The analogs also display immunologic activity and act as cytokine/trophokine modifiers, as anti-psoriatic or anti-allergic reagents.
The analogs of the invention also act as-a skin and/or tissue compatible coloring agent whose color can be influenced and modified by a number of factors such as degree of hydratization or derivativization (different salts exhibit different colors and the free acids also display different colors), the addition of other pigments, choice of the pH, or solvents. Color modification can be introduced with the appropriate choice of the cation. For example, for the analogs in which R1 is derived from carminic acid the magnesium, calcium, aluminum or other cations permit to vary the color from yellow to red to violet. Colored lacquers may be obtained, also varnishes for lipsticks, hair, nail coloring and other cosmetic uses (as additives to Mascara, or as Kajal additive). A number of analogs are fluorescent in a suitable environment. For example, the analogs in which R1 is derived from carminic acid display fluorescence emission at 575 mm. This can be used for hair coloring in clubs, discos and for show business. The colored hair fluoresces through light emission when illuminated in night clubs or by UV illumination, but the coloring agent protects from UV-introduced radical-mediated damages of hair or skin.
The new analogs are useful as ultra-radical scavengers and skin-protectors. In this respect, the analogs in which R1 is derived from xcex1-tocopherol is particularly useful as ultra-radical scavenger and also protects and stabilizes cosmetic cremes, lotions, essences or fluids. Therefore, the analogs of this invention are useful as multi-purpose stabilizers for many dermatological products (in ointments, creams, lotions, fluids, essences, special drug delivery systems such as sustained delivery systems for therapeutic, cosmetic or nutritional applications).
As radical-scavengers the new analogs also function as flexible skin-caring agents, protect against the influence of ultraviolet light, in particular in areas where there is an ozone deficiency. With these functions the new analogs are useful to prevent premature skin aging, modulate environmental stress and preserve humidity, and act as a humectant.
The new analogs act as wound-healing promoters and improve infection resistance.
The analogs in which R2 is derived from ubiquinone augment the respiratory activity of ubiquinone Q10 by modulating mitochondrial apoptosis. This results in preserving energy and enhances the rejuvenation process.
The analogs in which R1 is derived from glucuronic acid derivatives such as hyaluronic acid act as anti-oxidative skin protectors, as tissue clarifying agents, revitalize skin moisture by combining Vitamin B6 with hyaluronic acid. Their radical-scavenging and radiation protecting properties vitalize the human skin against environmental noxae, skin drying, and render the new analogs useful as sun protection factor with long-time efficiency.